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Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies.


ABSTRACT: Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fc? receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti-4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.

SUBMITTER: Madireddi S 

PROVIDER: S-EPMC4076583 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies.

Madireddi Shravan S   Eun So-Young SY   Lee Seung-Woo SW   Nemčovičová Ivana I   Mehta Amit Kumar AK   Zajonc Dirk M DM   Nishi Nozomu N   Niki Toshiro T   Hirashima Mitsuomi M   Croft Michael M  

The Journal of experimental medicine 20140623 7


Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agoni  ...[more]

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